GabaA benzodiazepine binding

Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ (1998) Decreased brain GABAA-benzodiazepine receptor binding in panic disorder. Arch Gen Psychiatry 55 715-720... 

Benzodiazepines all bind to a specific binding site on the gamma-aminobutyric acid (GABA) A chloride channel. The GABA chloride channel is a multi-subunit protein complex that is found in the plasma membrane of nerve cells in various parts of the CNS. When the neurotransmitter GABA binds to the chloride channel, the channel opens, allowing the influx of chloride ions into the cell. This causes hyperpolarization of the nerve cell and diminishes its response to excitatory input. The GABAa chloride channel is considered the major inhibitory system to neurotransmission in the CNS. 

Clonazepam, U5P. Clonazepam S-(2-chlorophenyl)-3-dihydro-7-nitro-2//-1,4-benzodiazpin-2-one (iCIonopin). partially selective at benzodiazepine allosteric binding sites on GABAa receptors, is useful in ab.sence seizures and in myoclonic seizures. Tolerance to the anticonvulsant effect often develops, a common problem with the benzodiazepines. Metabolism involves hydroxylation of the 3 position, followed by glucuronidation and nitro group reduction, followed by acetylation. 

Watt 62), one of the earlier researchers to recognize the potential of African plants in improving mental health, reported the use of Cotyledon orbiculata (Crassulaceae) leaves to treat epilepsy. Again, in vivo studies have demonstrated both aqueous and methanol extracts of C. orbiculata have anticonvulsant properties (moderate protection against pentylenetetrazole, bicuculline, picrotoxin and A-methyl-dl-aspartic induced seizures in mice) 63). However, the ethanolic extract did not show in vitro GABAA-benzodiazepine receptor binding activity 64). 

Hong, X. and Hopfinger, A.J. (2003) 3D-pharmacophores of fiavonoid binding at the benzodiazepine GABAA receptor site using 4D-QSAR analysis. J. Chem. Inf. Comput. Sci.,... 

Wieland HA, Liiddens H, Seeburg PH. A singie histidine in GABAa receptors is essentiai for benzodiazepine agonist binding, J Biol Chem 1992 267 1426-1429. 

Maddalena, D. J. and Johnston, G. A. R. (1995) Prediction of receptor properties and binding affinity of ligands to benzodiazepine/GABAA receptors using artificial neural networks. J. Med. Chem. 38, 715-724. 

GABAa is a protein with a pentameiic group of subunits (Fig. 4.7). Each subunit has approximately 200 amino acids. There are arormd fom hydrophobic regions which enable the receptor to possess allosteric pockets for interactions, and the hydrophobic region is also important to anchor the protein into the cell membrane. Barbiturates bind with a site different from the site of binding of benzodiazepines, which bind at the active site rather than changing the receptor conformation via an allosteric interaction. 

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

GABAa receptors that contain the al, a2, a3, and a5 subunits in combination with (3 and y subunits can bind classical benzodiazepines, e.g., diazepam, whereas GABAa receptors that contain the a4 and a6 subunits do not bind classical benzodiazepines. Essentially, all benzodiazepines that are currently in clinical use bind indiscriminately to GABAa receptors that contain the... 

Although flumazenil binds with high affinity to the benzodiazepine site of GABAa receptors, it has practically no action when given alone. However, flumazenil competitively blocks the action of benzodiazepine site agonists. Flumazenil can be used to terminate the action of benzodiazepines, e.g., after a benzodiazepine overdose. It may also serve as a diagnostic tool in this regard. 

The binding site for barbiturates on the GABAa receptor is less well defined. Barbiturates act by increasing the conductance level. In contrast to benzodiazepines, they also display direct agonistic action on GABAa receptors. Also in contrast to... 

Figure 19.7 The activity spectrum for different generic groups of compounds that bind to the benzodiazepine domain on the GABAa receptor...

Duggan, MJ and Stephenson, FA (1988) Benzodiazepine binding site heterogeneity in the purified GABAa receptor. Eur. J. Pharmacol. 154 293-298. 

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